1. Technical Field
The present invention relates to remedies for liver diseases such as acute hepatitis, chronic hepatitis, liver cirrhosis, and liver cancer.
2. Background Art
The liver is an organ having a strong regenerative power. In rats, when 70% of the liver parenchyma is removed, the remaining mesenchymal tissue begins to proliferate. Although this phenomenon, liver regeneration, has been considered to be induced by the participation of a certain humoral factor, the mechanism has remained unknown.
In 1984, Nakamura et al. discovered a hepatocyte growth factor (HGF) in blood of a rat having a liver that was in the course of regeneration (Nakamura, T. et al., "Biochem. Biophys. Res. Commun.", 122: 1450-1459, 1984). This discovery was achieved by use, as an index, of the DNA synthesis of hepatocytes of a mature rat in primary culture. Thereafter, cloning of the HGF cDNA satisfactorily led to the determination of the entire primary structure (Nakamura, T. et al., "Nature," 342: 440-443, 1989). As a result, HGF was found to be a new growth factor that has homology with no previously known growth factor whose structure had conventionally been clarified, such as epithelial growth factor (EGF), fibroblast growth factor (FGF), neuronal growth factor (NGF), platelet-derived growth factor (PDGF), or endothelial cell growth factor (ECGF).
In the meantime, Takahashi et al. cultured rat hepatocytes for a long period by use of an extract of epithelial mucosa of the bovine small intestine, and found that hepatocytes proliferate, through orderly aggregation and rearrangement of cells, form liver tissue-like construct and come to newly exhibit some of the liver functions (Takahashi, N. et al.: "In vitro Cellular & Developmental Biology, 25:365-372, 1989). Although there have been attempts to isolate and purify the growth factor contained in this extract and also to determine the structure of the growth factor, no such attempts have been successful so far.
The aforementioned HGF discovered by Nakamura et al. has been found to act as a potent mitogen not only on hepatocytes but also on primary culture of tubular epithelial cells, dermal keratinocytes and melanocytes, type II epithelial cells of pulmonary alveolus, and epithelial cells of gastric mucosa. In addition, it has also been elucidated that HGF has a function as a motogen to stimulate motion of cells as well as action to suppress proliferation of cancer cells.
Research and development of pharmaceuticals making use of diversified biological activities of HGF have currently performed actively. For example, clinical applications of HGF have been explored towards remedy and prevention of hepatitis and renal disorders, promotion of regeneration of the liver after hepatectomy, treatment of wounds, and use as anticancer agents. However, no efforts have been successful in using HGF in practical medicine.